Abstract 1007: Elucidating a role for the translation initiation factor, eIF4G1, in resistance to therapy in inflammatory breast cancer (IBC)

Abstract

Abstract Inflammatory breast cancer (IBC) is a highly invasive and aggressive breast cancer with relatively low survival rates compared with other locally advanced breast cancers. IBC is characterized by its rapid development of resistance to radio- and chemotherapies, which may in part be due to altered translational control driven by overexpression of the translation initiation factor, eIF4G1. This protein has been shown to enhance translation of eukaryotic mRNAs with internal ribosome entry sites (IRES) and enhanced translation in IBC may play a role in the survival of tumor cells during cellular stress, when translation would normally be suppressed. Some inhibitors of apoptosis proteins have 5′-untranslated regions (UTRs) that allow for IRES-mediated translation, and inhibition of apoptosis is one mechanism by which IBC cells have previously been shown to become resistant to therapy. Translational up-regulation of an inhibitor of apoptosis protein in therapy-resistant clones of IBC cell lines has been observed, which is of importance as the 5′UTR of such proteins contain highly active IRES elements. Regulation of such protein expression by eIF4G1-mediated IRES translation may be one reason for this observed therapeutic resistance. We knocked down eIF4G1 in a resistant IBC cell line (rSUM149) and assessed cellular viability after treatment with a powerful apoptosis inducer, TRAIL to evaluate the effect of targeted eIF4G1 knockdown on drug resistance in IBC. We observed that targeted knockdown of eIF4G1 sensitizes rSUM149 cells to TRAIL, significantly decreasing cellular viability. Additionally, using a novel culture system we show that inhibition of eIF4G1 expression decreases both the number of size of tumor emboli, a characteristic feature of IBC progression. These findings demonstrate a vital role for eIF4G1 for the development of therapeutic resistance and ultimately the aggressive pathobiology of IBC. Citation Format: Arianna Price, Courtney M. Edwards, Myron K. Evans, Gayathri Devi. Elucidating a role for the translation initiation factor, eIF4G1, in resistance to therapy in inflammatory breast cancer (IBC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1007. doi:10.1158/1538-7445.AM2015-1007